1. Field of the Invention
The present invention relates to cinnamohydroxamic acids as described further below. These compounds inhibit 5-lipoxygenase and are useful as bronchodilators.
2. Description of the Prior Art
N-unsubstituted cinnamohydroxamic acids have been described in the prior art. These include 3-substituted-4-alkoxycinnamohydroxamic acids wherein the 3 substituent may be hydrogen, halogen or alkoxy. See Buu-Hoi et al., J.Med.Chem. 13, 211 (1970). The compounds are said to have weak anti-inflammatory activity, and some compounds demonstrate antispasmodic activity. Tanaka et al., Chem.Pharm.Bull. 31, 2810 (1983) describe 4-methoxy-, 4-chloro-, 4-nitro- or 3,4-dimethoxy-cinnamohydroxamic acids which have anti-inflammatory and analgesic activity. Belgian Pat. No. 701,983 discloses substantially the same set of compounds, with the same utility, i.e., antiphlogistic, analgesic and antipyretic activity. French Pat. No. 1,461,338 describes some 3,4,5-trimethoxycinnamohydroxamic acids as "pharmaceutical intermediates".
Two references describe compounds which may be considered prodrugs of the above compounds. Paynard et al., Eur.J.Med. Chem. 10, 125 (1975) and French Pat. No. 2,190,430 describe various N-(dialkylaminomethyl)cinnamohydroxamic acids, with similar biological activities and potencies.
Szilagyi et al., Acta Pharm.Hung. 45, 49 (1975) discloses 3,5-dichloro-4-methoxy- and 3,5-methoxy-4-octyloxycinnamohydroxamic acids which were reported as having central nervous system (CNS) activity.
4-Acyl-2-alkyl-3-hydroxycinnamohydroxamic acids fall under the broad claims of European Pat. No. 132,366, which describes leukotriene antagonists useful for treating allergic disorders.
Similarly, N-substituted cinnamohydroxamic acids have also been described in the prior art. The N-methyl and N-t-butyl, ring-unsubstituted compounds have been disclosed. The former has been reported to be a vasodilator by Kehl et al., Arzneim.-Forsch. 28, 2087 (1978), while the latter was prepared by Jenkins et al., J.Chem.Soc.Perkin Trans. 2, 717 (1983) for physical-chemical studies. In addition, the N-(aminomethyl) derivatives (described above) and 3,4-dimethoxy-N-methylcinnamohydroxamic acid, prepared as an intermediate by Fountain et al. in Chem. and Biol. of Hydroxamic Acids, Proceedings of the First International Symposium, H. Kehl, ed., Karger (Basel), pp. 51-62 (1982) have been disclosed in the prior art. The broad claims of European Pat. No. 132,366 (described above) include N-alkyl derivatives. A few N,O-dialkylcinnamohydroxamic acids are claimed as CNS depressants in French Pat. No. 1,332,352.
Finally, several references describe compounds which have been disclosed to inhibit lipoxygenases. U.S. Pat. Nos. 4,623,661, 4,605,669 and 4,608,380, as well as European Pat. No. 199,151, describe compounds having the formula ##STR1## where R is a trinuclear aromatic group, a binuclear aromatic group or a substituted naphthyl group.
European Pat. No. 196,184 describes an exceedingly vast array of compounds which may include cinnamohydroxamic acids, such as N,4-methylcinnamohydroxamic acid. The generic disclosure includes compounds of the above formula where R is phenyl or phenyl substituted by alkyl, alkoxy, halogen, nitro, amino or hydroxy. Although the compounds are said to be useful in treating a large variety of disorders (see column 13, line 21--column 14, line 36 and column 15, line 1--column 18, line 4), no specific disclosure of activity other than for cut flowers is provided.